Diagnosis of respiratory tract infectious diseases using urine specimens

ABSTRACT

According to the method for detecting respiratory infection associated with bacterial infection of the present invention, the measured value of soluble CD14 antigen subtype (“sCD14-ST) in the urine sample can be used to select a patient with a respiratory infection to whom the antibiotic can be administered.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application of PCT/JP2012/062797,filed May 18, 2012, which claims priority from Japanese application JP2011-112699, filed May 19, 2011.

TECHNICAL FIELD

The present invention relates to a method for detecting respiratoryinfection associated with bacterial infection, a method for selectingpatients with respiratory infection to receive an antibiotic, and amethod for determining the timing for ending administration of anantibiotic to a patient with respiratory infection receiving theantibiotic. In addition, the present invention also relates to a methodfor treating respiratory infection associated with bacterial infection.

BACKGROUND ART

Respiratory infection is a disease frequently encountered in clinicalsites. There are two types of respiratory infection, namely, respiratoryinfection caused by viral infection and respiratory infection caused bybacterial infection. Antibiotics have no effects on viral respiratoryinfection. In principle, upon administration of antibiotics, a causativemicroorganism is first identified, and an antibiotic used therefor isthen selected depending on the sensitivity of the causativemicroorganism to drugs, etc. However, since it takes a long period oftime to search for such a causative microorganism by blood culture orexamination of sputum, in reality, a treatment using antibiotics hasbeen started before determination of a pathogen in almost all cases.Moreover, since the detection sensitivity of bacteria is not necessarilyhigh in such blood culture or examination of sputum, even if the resultsare negative, bacterial infection cannot be denied. Thus, antibioticsare used even for patients with respiratory infection suspected to havebacterial infection. Hence, administration of antibiotics to patientswho do not need them causes an increase in resistant bacteria (NonPatent Literature 1).

For the proper use of antibiotics, it is necessary that the presence orabsence of bacterial infection in respiratory infection can be promptlyand precisely diagnosed in clinical sites. As such a diagnostic marker,the usefulness of procalcitonin has been studied. It has been reportedthat when lower respiratory tract infection or pneumonia is treated withantibiotics, while using the concentration of procalcitonin in blood asan indication, the amounts of the antibiotics used can be decreased (NonPatent Literature 2 and Non Patent Literature 3).

Procalcitonin has also been used as a diagnostic marker for sepsis. Inthis case, procalcitonin is used as an indication, such that when theprocalcitonin concentration in blood is 0.5 ng/mL or higher, the subjectis determined to have sepsis, and when the procalcitonin concentrationis 2.0 ng/mL or higher, the subject is determined to have severe sepsis.On the other hand, when procalcitonin is used as a marker for lowerrespiratory tract infection or pneumonia, a change in a bloodprocalcitonin concentration that ranges from 0.1 to 0.5 ng/mL must bedetected, and thus, there is a restriction that a highly sensitive assaymust be used. Moreover, it has also been reported that, sinceprocalcitonin is stably present in blood, the blood procalcitoninconcentration is relatively slowly lowered even in a case in which thetreatment has been successful (Patent Literature 1). It is consideredthat when the half-life of procalcitonin in blood is long, aconcentration change is hardly detected.

As a novel marker for sepsis that is superior to procalcitonin, theusefulness of sCD14-ST (soluble CD14 antigen subtype; alias name:presepsin) has been studied. It has been reported that even if suchsCD14-ST is used in a comparison between a patient with sepsis and apatient with systemic inflammatory response syndrome (SIRS) that isdifficult to be distinguished from sepsis, it shows a high value in theblood of the sepsis patient. Thus, it has been considered that sCD14-STis useful as a diagnostic marker for sepsis (Non Patent Literature 4 andPatent Literature 2).

Furthermore, it has also been reported that sCD14-ST is generated in aprocess in which cells englobe and digest foreign microorganisms orforeign matters, and that an increase in the concentration of sCD14-STin synovial fluid can be detected in a disease that involvesphagocytosis attended with autoimmune response or infection in localsites, such as arthritis (Patent Literature 3).

CITATION LIST Patent Literature

-   Patent Literature 1: International Publication WO2008/104321-   Patent Literature 2: International Publication WO2005/108429-   Patent Literature 3: International Publication WO2009/142303

Non Patent Literature

-   Non Patent Literature 1: Ball et al., Journal of Antimicrobial    Chemotherapy 49: 31-40, 2002.-   Non Patent Literature 2: Christ-Crain et al., The Lancet 363:    600-607, 2004.-   Non Patent Literature 3: Christ-Crain et al., Am J Respire Crit Care    Med 174: 84-93, 2006.-   Non Patent Literature 4: Yaegashi et al. Journal of Infection and    Chemotherapy 11: 234-238, 2005.

SUMMARY OF INVENTION Technical Problem

It is an object of the present invention to provide a method forappropriately selecting patients with respiratory infection to whom anantibiotic is to be administered, and a method for adjusting theadministration period of an antibiotic. That is to say, the presentinvention is directed towards achieving the object that is the properuse of antibiotics for respiratory infection. Specifically, the presentinvention provides a method for detecting respiratory infectionassociated with bacterial infection, a method for selecting patientswith respiratory infection to receive an antibiotic, and a method fordetermining the timing for ending administration of an antibiotic to apatient with respiratory infection receiving the antibiotic. To achievethese objects, it has been desired to develop a novel marker used toappropriately select respiratory infection associated with bacterialinfection. In addition, it has also been desired to develop a sensitivemarker, the concentration of which promptly decreases with diminutionand/or disappearance of bacterial infection in respiratory organs.Moreover, the present invention provides a method for treatingrespiratory infection associated with bacterial infection.

Solution to Problem

The present inventor has found that it becomes possible to appropriatelyselect patients with respiratory infection to whom an antibiotic is tobe administered, and also to adjust the administration period of anantibiotic, by using a measured value of sCD14-ST in urine as anindication, thereby completing the present invention.

More specifically, the present invention includes the followingfeatures.

The present invention provides the following methods for detectingrespiratory infection associated with bacterial infection:

(1-1) A method for detecting respiratory infection associated withbacterial infection, comprising measuring sCD14-ST in a urine samplederived from a subject.

(1-2) A method for detecting respiratory infection associated withbacterial infection, which comprises the following steps of:

1) measuring sCD14-ST in a urine sample derived from a subject; and

2) determining whether or not the subject is affected with respiratoryinfection associated with bacterial infection by using a measured valueof sCD14-ST in the sample as an indication.

(1-3) A method for detecting respiratory infection associated withbacterial infection, which comprises the following steps of:

1) measuring sCD14-ST in a urine sample derived from a subject;

2) comparing a measured value of sCD14-ST in the sample with a normalvalue; and

3) determining whether the measured value of the sample is higher thanthe normal value.

(1-4) The method according to above (1-3), wherein, as the normal value,an average value of measured values of sCD14-ST in urine samples ofnormal subjects+2SD is used.

(1-5) A method for detecting respiratory infection associated withbacterial infection, comprising the step of:

1) measuring sCD14-ST in a urine sample derived from a subject.

(1-6) The method for detecting according to above (1-5), which furthercomprises the following step of:

2) comparing the measured value of sCD14-ST in the urine sample with anormal value.

(1-7) The method for detecting according to above (1-6), which furthercomprises the following step of:

3) determining whether the measured value is higher than the normalvalue or not.

(1-8) The method according to any of above (1-1) to (1-7), wherein therespiratory infection associated with bacterial infection is lowerrespiratory tract infection or pneumonia.

(1-9) The method according to any of above (1-1) to (1-8), wherein adifferential diagnosis of respiratory infection caused by viralinfection is possible.

(1-10) The method according to any of above (1-1) to (1-9), wherein, inaddition to measurement of sCD14-ST in a urine sample derived from asubject, at least one kind of causative microorganism test is performed.

(1-11) The method according to above (1-10), wherein the causativemicroorganism test is at least one selected from the group consisting ofstained smear test, antigen test of influenza virus, adenovirus,legionella, chlamydia, mycoplasma, aspergillus, candida, cryptococcus,cytomegalovirus, or pneumococcus, and culture test of blood, sputum orbronchioalveolar lavage fluid.(1-12) A marker for respiratory infection associated with bacterialinfection, comprising sCD14-ST.(1-13) The marker according to above (1-12), further comprising at leastone selected from the group consisting of inflammation markers includingTNF-α, lactate dehydrogenase, sialic acid, IL-1β, IL-6, and IL-10,markers associated with thrombus and hemostasis including activatedpartial thromboplastin time, platelet count, fibrinogen, items of thediagnostic criteria for DIC, protein C, D-dimer, thrombin-antithrombinIII complex, and prothrombin fragment F1+2, infection markers includingprocalcitonin (PCT), C-reactive protein (CRP), blood urea nitrogen,white blood cell count, endotoxin, adrenomedullin, proadrenomedullin,MR-proADM, B-type natriuretic peptide, trigger receptors expressed onmyeloid cell-1, and HMGB1, stress markers including cortisone andcopeptin, and markers for interstitial pneumonia including KL-6, SP-A,SP-D, and MCP-1.(1-14) A method for detecting respiratory infection associated withbacterial infection, wherein sCD14-ST in a urine sample derived from asubject and at least one biomarker other than sCD14-ST are measured.(1-15) The method according to above (1-14), wherein the biomarker otherthan sCD14-ST is at least one marker stated in above (1-13).

The present invention provides the following methods for selectingpatients with respiratory infection to receive an antibiotic:

(2-1) A method for selecting patients with respiratory infection toreceive an antibiotic, comprising: measuring sCD14-ST in urine samplesderived from patients.

(2-2) A method for selecting patients with respiratory infection toreceive an antibiotic, which comprises the following steps of:

1) measuring sCD14-ST in urine samples derived from patients; and

2) determining whether or not patients are affected with respiratoryinfection associated with bacterial infection by using measured valuesof sCD14-ST in the samples as an indication.

(2-3) A method for selecting patients with respiratory infection toreceive an antibiotic, which comprises the following steps of:

1) measuring sCD14-ST in urine samples derived from patients;

2) comparing measured values of sCD14-ST in the samples with a normalvalue; and

3) determining whether the measured values of the samples are higherthan the normal value.

(2-4) The method according to above (2-3), wherein, as the normal value,an average value of measured values of sCD14-ST in urine samples ofnormal subjects+2SD is used.

(2-5) The method according to any of above (2-1) to (2-4), wherein therespiratory infection is lower respiratory tract infection or pneumonia.

The present invention provides the following methods for determining thetiming for ending administration of an antibiotic to a patient withrespiratory infection receiving the antibiotic.

(3-1) A method for determining the timing for ending administration ofan antibiotic to a patient with respiratory infection receiving theantibiotic, wherein a measured value of sCD14-ST in a urine samplederived from the patient is used as an indication.

(3-2) A method for determining the timing for ending administration ofan antibiotic to a patient with respiratory infection receiving theantibiotic, which comprises the following steps of:

1) measuring sCD14-ST in a urine sample derived from a patient;

2) comparing the measured value of sCD14-ST in the sample with apredetermined reference value; and

3) when the measured value of the sample is lower than the predeterminedreference value, determining to end administration of the antibiotic.

(3-3) The method according to above (3-2), wherein, as the predeterminedreference value, an average value of measured values of sCD14-ST inurine samples of normal subjects+SD is used.

(3-4) A method for selecting patients to end administration of anantibiotic from patients with respiratory infection receiving theantibiotic by using measured values of sCD14-ST in urine samples derivedfrom patients as indications.

(3-5) A method for selecting patients to end administration of anantibiotic from patients with respiratory infection receiving theantibiotic, which comprises the following steps of:

1) measuring sCD14-ST in urine samples derived from patients;

2) comparing measured values of sCD14-ST in samples with a predeterminedreference value; and

3) when the measured values of the samples are lower than thepredetermined reference value, determining to end administration of theantibiotic.

(3-6) The method according to above (3-5), wherein, as the predeterminedreference value, an average value of measured values of sCD14-ST inurine samples of normal subjects+SD is used.

(3-7) The method according to any of above (3-1) to (3-6), wherein therespiratory infection is lower respiratory tract infection or pneumonia.

The present invention provides the following treating methods ofrespiratory infection associated with bacterial infection.

(4-1) A method for treating respiratory infection associated withbacterial infection, which comprises the following steps of:

1) measuring sCD14-ST in urine samples derived from patients;

2) selecting patients to receive an antibiotic by using measured valuesof sCD14-ST in the samples as an indication; and

3) administering the antibiotic to the selected patients.

(4-2) The method according to above (4-1), wherein the step of selectingpatients to receive an antibiotic by using measured values of sCD14-STin the samples as an indication comprises the following steps of:

1) comparing measured values of sCD14-ST in the samples with a normalvalue; and

2) selecting patients to receive an antibiotic whose measured values insamples are higher than the normal value.

(4-3) The method according to above (4-2), wherein, as the normal value,an average value of measured values of sCD14-ST in urine samples ofnormal subjects+2SD is used.

(4-4) The method according to any of above (4-1) to (4-3), which furthercomprises the following steps of:

1) measuring over time sCD14-ST in urine samples derived from patientsreceiving an antibiotic;

2) comparing measured values of sCD14-ST in samples with a predeterminedreference value; and

3) when the measured values of the samples are lower than thepredetermined reference value, determining to end administration of theantibiotic.

(4-5) The method according to above (4-4), wherein, as the predeterminedreference value, an average value of measured values of sCD14-ST inurine samples of normal subjects+SD is used.

(4-6) The method according to any of above (4-1) to (4-5), wherein therespiratory infection associated with bacterial infection is lowerrespiratory tract infection or pneumonia.

The present invention provides the following compositions for treatingrespiratory infection associated with bacterial infection.

(5-1) A composition for treating respiratory infection associated withbacterial infection, comprising an antibiotic as an active ingredient,wherein the composition is used so that sCD14-ST in a urine samplederived from a patient with suspected respiratory infection associatedwith bacterial infection is measured, the measured value is comparedwith a normal value, and when the measured value in the sample is higherthan the normal value, the composition is administered to the patient.(5-2) The composition for treating respiratory infection associated withbacterial infection according to above (5-1), wherein, as the normalvalue, an average value of measured values of sCD14-ST in urine samplesof normal subjects+2SD is used.(5-3) A composition for treating respiratory infection associated withbacterial infection, comprising an antibiotic as an active ingredient,wherein the composition is used so that sCD14-ST in a urine samplederived from a patient with suspected respiratory infection associatedwith bacterial infection is measured, the measured value is comparedwith a normal value, and when the measured value in the sample is higherthan the normal value, the composition is administered to the patient,and sCD14-ST in urine samples during an administration period ismeasured over time, and when a measured value is lower than apredetermined value, administration of the composition is ended.(5-4) The composition for treating respiratory infection associated withbacterial infection according to above (5-3), wherein, as the normalvalue, an average value of measured values of sCD14-ST in urine samplesof normal subjects+2SD, and as the predetermined reference value, anaverage value of measured values of sCD14-ST in urine samples of normalsubjects+SD are used.(5-5) The composition for treating respiratory infection associated withbacterial infection according to any of above (5-1) to (5-4), whereinthe respiratory infection associated with bacterial infection is lowerrespiratory tract infection or pneumonia.(6) The method, marker, or composition according to any of above (1-1)to (5-5), wherein, in measurement of sCD-14 in the urine sample, anaverage value of measured values of patients with pneumonia associatedwith bacterial infection is higher than that of normal subjects, and anaverage value of measured values of patients with viral pneumonia islower than that of normal subjects.(7) The method, marker, or composition according to any of above (1-1)to (6), wherein, with regard to the measurement of sCD-14 in the urinesample, the concentration of sCD-14 in a blood sample derived from thesame subject is measured, and the two measured values are then comparedwith each other.

Effects of Invention

According to the present invention, by using a measured value ofsCD14-ST in urine as an indication, it becomes possible to appropriatelyselect patients with respiratory infection to whom an antibiotic is tobe administered, and also to adjust the administration period of theantibiotic. Antibiotics should be administered to diseases attended withbacterial infection. By measuring the concentration of sCD14-ST inurine, patients having respiratory infection associated with bacterialinfection can be detected with high specificity and/or high sensitivity.Moreover, by determining the timing for ending administration of anantibiotic using a measured value of sCD14-ST in urine as an indication,the administration period of the antibiotic can be reduced. The properuse of an antibiotic for respiratory infection using a measured value ofsCD14-ST in urine as an indication is useful in that it enablessuppression of the emergence of multi-drug-resistant bacteria, areduction in the treatment period, a reduction in the amount of theantibiotic used, and a reduction in medical costs, without impairing thesafety and usefulness thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a view illustrating a standard curve of the sCD14-STmeasurement system produced in Example 1.

FIG. 2 is a view illustrating a distribution of the sCD14-STconcentrations in urine of pneumonia patients measured in Example 2. Thehorizontal axis indicates the number of days elapsed from the diagnosisof pneumonia to collection of the samples, and the longitudinal axisindicates the sCD14-ST concentration in urine. In the figure, the solidline indicates an average value (3338 pg/mL) of healthy subjects, andthe dotted line indicates an average value+2SD (5758 pg/mL) of healthysubjects.

FIG. 3 is a view illustrating a distribution of the sCD14-STconcentrations in urine of pneumonia patients with bacterial infectionand pneumonia patients with viral infection, which were measured inExample 5. The longitudinal axis indicates the sCD14-ST concentration inurine.

FIG. 4 is a view illustrating a transition in the sCD14-STconcentrations in blood and a transition in the sCD14-ST amounts inurine in the case of intravenous administration of sCD14-ST, which weremeasured in Example 6. The horizontal axis indicates the time elapsedafter completion of the administration. The left longitudinal axisindicates the sCD14-ST amount in urine, and the right longitudinal axisindicates the sCD14-ST concentration in blood.

DESCRIPTION OF EMBODIMENTS

Hereinafter, the present invention will be described in detail.

1. sCD14-ST

sCD14-ST (alias name: presepsin) is a molecular species of soluble CD14.sCD14-ST is characterized in that the molecular weight measured bySDS-PAGE under non-reducing conditions is 13±2 kDa, and it retains anN-terminal portion of CD14. In addition, when such sCD14-ST is comparedwith the entire-length CD14, it has an amino acid sequence comprising asignificant deletion on the C-terminal side thereof, and the two aboveproteins are different from each other in terms of conformation. Thus,they exhibit different immunogenicity. As such, the two proteins can bedistinguished from each other based on antibodies to which they bind.sCD14-ST has a property that it specifically binds to an antibodyproduced using a peptide consisting of the 16 amino acid residues shownin SEQ ID NO: 2 as an antigen. Moreover, sCD14-ST can have any given oneor more characteristics selected from that it specifically binds to apeptide consisting of the amino acids at positions 17 to 26 of the aminoacid sequence shown in SEQ ID NO: 3, that it does not bind to a 3C10antibody, that it does not bind to an MEM-18 antibody, that it does nothave LPS-binding ability, and that it can be obtained from human blood.Also, sCD14-ST is characterized in that it has the amino acid sequenceshown in SEQ ID NO: 1 as an N-terminal sequence thereof. Morespecifically, sCD14-ST can be specified by the characteristics that theN-terminus of sCD14-ST is the amino acid at position 1 of the amino acidsequence shown in SEQ ID NO: 3, and that the C-terminus thereof is anyone of the amino acids at positions 59 to 90 of the amino acid sequenceshown in SEQ ID NO: 3. Such sCD14-ST is disclosed in detail inInternational Publication WO2005/108429. The term “sCD14-ST” is used inthe present specification to mean human sCD14-ST, unless otherwisespecified.

For the measurement of sCD14-ST in a urine sample, an immune measurementsystem for specifically detecting sCD14-S, which is disclosed inInternational Publication WO2004/044005 or International PublicationWO2005/108429, can be used, for example. Specifically, a sandwichimmunoassay system comprising a combination of an antibody producedusing a peptide consisting of the 16 amino acid residues shown in SEQ IDNO: 2 as an antigen with an antibody binding to a peptide consisting ofthe amino acids at positions 17 to 26 of the amino acid sequence shownin SEQ ID NO: 3 or with an antibody competitive to the aforementionedantibody (an F1106-13-3 antibody or an F1031-8-3 antibody) can be used.

The measured value of sCD14-ST in a urine sample can be generallyindicated as a sCD14-ST concentration in urine. Upon calculation of thesCD14-ST concentration in urine, the measured value of sCD14-ST may becorrected based on the concentration of the urine according to thecreatinine correction or the like. Moreover, the measured value ofsCD14-ST may be any one of a quantitative value, a semiquantitativevalue, and a qualitative value. When such a semiquantitative value isused, the sCD14-ST concentration can be indicated as a stage of 0, 1, 2and 3, or of +, ++ and +++. Since this stage correlates to thequantitative sCD14-ST concentration, whether or not the obtainedsCD14-ST concentration is higher than the predetermined reference valuemay be determined based on the correlation of the semiquantitative stagewith the quantitative sCD14-ST concentration. Otherwise, in the case ofa semiquantitative assay, the value lower than the reference value maybe set at a stage of 0 or −(minus). When a quantitative value is used,the value lower than the reference value may be set at negative, and thevalue higher than the reference value may be set at positive.

Urine sCD14-ST means blood sCD14-ST that has been eliminated into urine.Blood sCD14-ST is relatively promptly eliminated into urine after it hasbeen generated. Moreover, since sCD14-ST contained in circulating bloodis concentrated and is then eliminated in urine, the sCD14-STconcentration in urine is higher than the sCD14-ST concentration inblood. Accordingly, by using the measured value of sCD14-ST in a urinesample as an indication, the presence or absence of bacterial infectionin respiratory organs can be sensitively detected.

2. Method for Detecting Respiratory Infection Associated with BacterialInfection

The present invention provides a method for detecting respiratoryinfection associated with bacterial infection, which comprises measuringsCD14-ST in a urine sample derived from a subject.

Preferred examples of the respiratory infection associated withbacterial infection include lower respiratory tract infection andpneumonia.

The lower respiratory tract infection includes acute lower respiratorytract infection and chronic lower respiratory tract infection. The acutelower respiratory tract infection includes acute tracheitis, acutebronchitis, and acute bronchiolitis. A majority of these diseasesdevelop as a result of expansion of the viral infection of the upperrespiratory tract to the lower respiratory tract. In some of thesediseases, secondary infection by bacteria then takes place. When thesymptoms of such secondary infection by bacteria are found,administration of antibiotics is applied. The chronic lower respiratorytract infection is a pathologic condition in which persistent bacterialinfection has been found in the lower respiratory tract having organicdisorders caused by bronchiectasis or chronic obstructive pulmonarydisease, and it includes persistent infection and acute exacerbation.Diseases causing organic disorders to the lower respiratory tractinclude bronchiectasis, chronic obstructive pulmonary disease, chronicbronchitis, diffuse panbronchiolitis, obsolete pulmonary tuberculosis,pneumoconiosis, nontuberculous mycobacterial infection, allergicbronchopulmonary aspergillosis, lung fibrosis, and chronic bronchialasthma. In both cases of persistent infection and acute exacerbation,administration of antibiotics is applied.

Pneumonia includes community-acquired pneumonia and hospital-acquiredpneumonia. In the present invention, community-acquired pneumonia ispreferable.

The type of a subject is not particularly limited herein. A preferredsubject is a person suspected to have respiratory infection based onclinical findings. Such clinical findings include at least dyspnea orcoughing. In addition, preferred clinical findings include at least oneselected from the group consisting of expectoration, chest pain,wheezing, shadow in chest X-ray examination, fever, and white blood cellcount.

The method for detecting respiratory infection associated with bacterialinfection of the present invention is characterized in that it comprisesthe following steps of: 1) measuring sCD14-ST in a urine sample derivedfrom a subject; and 2) determining whether or not the subject isaffected with respiratory infection associated with bacterial infectionby using a measured value of sCD14-ST in the sample as an indication.More specifically, the aforementioned step 2) may comprise the followingsteps of: 3) comparing a measured value of sCD14-ST in the sample with anormal value; and 4) determining whether the measured value of thesample is higher than the normal value.

By comparing a measured value of sCD14-ST in the sample with thepredetermined reference value, whether or not the subject hasrespiratory infection associated with bacterial infection can bedetermined. The reference value used in the method for detectingrespiratory infection associated with bacterial infection of the presentinvention is preferably a normal value that has been set based on themeasured value of sCD14-ST in a urine sample derived from a healthysubject. As such a normal value, an average value of the measurementresults of sCD14-ST in the urine samples of healthy subjects, or a valuestandardized by defining the scope, etc., can be used. When the measuredvalue of a sample derived from a healthy subject is almost the same asthe value of the background in a measurement system, an average value ofthe background values in the measurement system, or a value standardizedby defining the scope, etc., may be used. The background value in themeasurement system means a measured value obtained in a case in whichnot a sample but a buffer, an assay solution or the like has been addedto the measurement system. As a value obtained by standardization of themeasured values of samples derived from subjects, an average value+0.5SDto +5SD (SD: standard deviation) of the measured values of healthysubjects, 5 to 95, 10 to 90, 15 to 85, or 25 to 75 percentile of themeasured values of healthy subjects, or the like can be used. Apreferred value is an average value+SD, +2SD or +3SD of the measuredvalues of healthy subjects.

Upon setting a normal value based on the measured values of sCD14-ST inurine samples from healthy subjects, the value of sCD14-ST in a urinesample derived from a patient having respiratory infection associatedwith bacterial infection, which has previously been measured, may beused as a reference. In this case, a cutoff value that optimizes thesensitivity and/or specificity in detection of a disease can be used asa normal value. It is, for example, 5000 pg/mL.

When the measured value of a sample derived from a subject is comparedwith a normal value, and the measured value of the sample is higher thanthe normal value, it can be determined that the subject is highly likelyto be affected with respiratory infection associated with bacterialinfection, namely, the subject is positive. Moreover, as the measuredvalue increases, it can be determined that the grade of the diseaseand/or the severity of the disease are/is high.

Since sCD14-ST is hardly generated in blood in the case of viralrespiratory infection without bacterial infection, the sCD14-STconcentration in urine does not increase, either. Thus, by measuringsCD14-ST in a urine sample, respiratory infection associated withbacterial infection can be distinguished from viral respiratoryinfection.

Furthermore, in the method for detecting respiratory infectionassociated with bacterial infection of the present invention, at leastone causative microorganism test may be carried out, in addition to themeasurement of sCD14-ST in a urine sample derived from a subject. Assuch a causative microorganism test, a method may be appropriatelyselected from known methods such as a stained smear test, an antigentest and a culture test, and may be then used.

Further, in the method for detecting respiratory infection associatedwith bacterial infection of the present invention, at least onebiomarker other than sCD14-ST may be measured, in addition to themeasurement of sCD14-ST in a urine sample derived from a subject. Assuch a biomarker other than sCD14-ST, a suitable marker may be selectedfrom among an inflammatory marker, a thrombosis/hemostasis-relatedmarker, an infection marker, an interstitial pneumonia marker and thelike, and it may be then used. Preferred examples of such a biomarkerinclude, but are not limited to, procalcitonin, a C-reactive protein(CRP) and KL-6.

The method for detecting respiratory infection associated with bacterialinfection of the present invention can also be referred to as a methodfor selecting patients with respiratory infection to receive anantibiotic. A subject in whom respiratory infection associated withbacterial infection has been detected is a patient who is highly likelyto be affected with the respiratory infection associated with bacterialinfection, and thus, the subject can be a preferred target foradministration of antibiotics. Among such patients suspected to haverespiratory infection based on clinical findings, patients to whomantibiotics are to be administered are those having respiratoryinfection associated with bacterial infection. By using a measured valueof sCD14-ST in a urine sample as an indication, the presence or absenceof respiratory infection associated with bacterial infection can bedetected, and thus, it has become possible to select patients withrespiratory infection to whom antibiotics are to be administered. Thatis to say, the present invention provides a method for selectingpatients with respiratory infection to receive an antibiotic, which ischaracterized in that it comprises measuring sCD14-ST in a urine samplederived from a patient. To the method for selecting patients withrespiratory infection to receive an antibiotic of the present invention,the aspect of the method for detecting respiratory infection associatedwith bacterial infection can directly be applied.

3. Method for Determining the Timing for Ending Administration of anAntibiotic to a Patient with Respiratory Infection Receiving theAntibiotic

The present invention provides a method for determining the timing forending administration of an antibiotic to a patient with respiratoryinfection receiving the antibiotic, wherein a measured value of sCD14-STin a urine sample derived from the patient is used as an indication.

The type of a patient, to whom the method for determining the timing forending administration of an antibiotic of the present invention isapplied, is not particularly limited, as long as he/she is a patientwith respiratory infection to whom an antibiotic has been administered.A preferred example is a subject, in whom respiratory infectionassociated with bacterial infection has been detected by the methoddescribed in 2. above, and who has been selected as a patient withrespiratory injection to whom an antibiotic is administered.

The method for determining the timing for ending administration of anantibiotic of the present invention is characterized in that itcomprises the following steps of: 1) measuring sCD14-ST in a urinesample derived from a patient; and 2) determining the timing for endingadministration of an antibiotic to the patient by using a measured valueof sCD14-ST in the sample derived as an indication. More specifically,the aforementioned step 2) may comprise the following steps of: 3)comparing the measured value of sCD14-ST in the sample with apredetermined reference value; and 4) when the measured value of thesample is lower than the predetermined reference value, determining toend administration of the antibiotic.

In the method for determining the timing for ending administration of anantibiotic of the present invention, when sCD14-ST in a urine samplederived from a patient is measured, it may be measured over time. Ingeneral, in the case of respiratory infection associated with bacterialinfection, antibiotics are administered over a period of approximately 5to 14 days. In order to reduce a burden on a patient and prevent theemergence of resistant bacteria, it is desired to terminateadministration of an antibiotic as soon as the healing or improvement ofinfection can be confirmed. By measuring sCD14-ST over time, the timingfor ending administration of an antibiotic can be more accuratelydetermined. Since the sCD14-ST concentration in urine promptly decreaseswith diminution and/or disappearance of bacterial infection inrespiratory organs, it is useful as an indication for determiningtermination of the treatment. The measurement period may beappropriately set. It may be set, for example, at every day, every twodays, or on the 3^(rd) day, 5^(th) day or 7^(th) day after initiation ofthe administration of an antibiotic.

Since a measured value of sCD14-ST in the sample is used as anindication for the presence or absence of bacterial infection in thepatient, when the measured value of the sample is lower than thepredetermined reference value, it can be determined that the infectionhas been healed or improved, thereby determining to end administrationof the antibiotic. The reference value used in the method fordetermining the timing for ending administration of an antibiotic of thepresent invention is not particularly limited, as long as it can be usedto confirm that the antibiotic has been effective. For instance, a valuethat is ½, ⅕ or 1/10 of the sCD14-ST value measured over a period frombefore administration of the antibiotic to 24 hours after initiation ofthe administration of the antibiotic can be used as a reference value.Otherwise, a normal value set based on the measured value of sCD14-ST ina urine sample derived from a healthy subject, as described in theaspect of 2. above, can also be used as a reference value. For example,it is an average value+SD, +2SD, or +3SD of healthy subjects. If themeasured value of sCD14-ST is in the range of normal values, it can beconsidered that the infection has been healed or improved to a levelequivalent to healthy subjects. Preferably, using the previouslymeasured values of sCD14-ST in urine samples derived from healthysubjects and from patients having respiratory infection associated withbacterial infection, a cutoff value is set such that the sensitivityand/or specificity in detection of a disease can be optimized. The thusset cutoff value can be used as a reference value. It is, for example,5000 pg/mL.

The method for determining the timing for ending administration of anantibiotic of the present invention can also be referred to as a methodfor selecting patients to end administration of an antibiotic frompatients with respiratory infection receiving the antibiotic. Bydetermining the timing for ending administration of an antibiotic, apatient becomes a target for ending administration of the antibiotic.Thus, the method for determining the timing for ending administration ofan antibiotic has the same meanings as those of the method for selectingpatients to end administration of an antibiotic. That is to say, thepresent invention provides a method for selecting patients to endadministration of an antibiotic from patients with respiratory infectionreceiving the antibiotic by using measured values of sCD14-ST in urinesamples derived from patients as indications. To the method forselecting patients to end administration of an antibiotic of the presentinvention, the aspect of the method for determining the timing forending administration of an antibiotic can directly be applied.

4. Method for Treating Respiratory Infection Associated with BacterialInfection

The present invention provides a method for treating respiratoryinfection associated with bacterial infection. The treatment method ofthe present invention is characterized in that it comprises selectingpatients with respiratory infection to receive an antibiotic by usingthe measured value of sCD14-ST in a urine sample derived from a subjectas an indication, and this is a method for treating respiratoryinfection associated with bacterial infection by administering anantibiotic to the thus selected patients. Specifically, patients withrespiratory infection to receive an antibiotic are selected by themethod described in the aspect of 2. above, and the antibiotic is thenadministered to selected patients. Moreover, the timing for endingadministration of an antibiotic is determined by the method described inthe aspect of 3. above, so as to provide a more efficient treatment.

Moreover, the present invention provides a therapeutic agent (or atherapeutic pharmaceutical composition) for treating respiratoryinfection associated with bacterial infection, which is characterized inthat it uses an antibiotic by a usage that is in accordance with theabove-mentioned treatment method. The present therapeutic compositioncomprises an antibiotic as an active ingredient. The present therapeuticcomposition may comprise pharmaceutically acceptable any given additivesand/or carriers, as well as an effective amount of antibiotic.

The types of antibiotics used in the inventions according to the aspectsdescribed in 2. to 5. above are not particularly limited. Antibioticsthat can be applied to at least lower respiratory tract infection and/orpneumonia are preferable. Examples of such an antibiotic includepenicillin antibiotics, penem antibiotics, carbapenem antibiotics,cephem antibiotics, monobactam antibiotics, fosfomycin antibiotics,glycopeptide antibiotics, aminoglycoside antibiotics, macrolideantibiotics, ketolide antibiotics, lincomycin antibiotics, tetracyclineantibiotics, new quinolone antibiotics, sulfonamide antibiotics,oxazolidinone antibiotics, and streptogramin antibiotics. One ormultiple antibiotics may be appropriately selected from theseantibiotics and may be then used. For selection of antibiotics, knownmethods such as the method described in the Japanese RespiratorySociety, “The Japanese Respiratory Society Guidelines for Management ofAdult Community-Acquired Pneumonia” (Asu no Rinsho, Vol. 19, No. 1, pp.41-61, 2007) may be applied.

Hereinafter, the present invention will be more specifically describedin the following examples. However, these examples are not intended tolimit the scope of the present invention.

EXAMPLES Example 1 Production of sCD14-ST Measurement System

(1-1) Preparation of Peroxidase-Labeled Antibody

In order to produce a sandwich ELISA system, the F1106-13-3 antibodydescribed in International Publication WO2004/044005 was labeled withperoxidase. First, the F1106-13-3 antibody was digested with LysylEndopeptidase (Wako Pure Chemical Industries, Ltd.) to produce F(ab′)2.Specifically, the F1106-13-3 antibody was dialyzed against 50 mMTris-HCl (pH 8.5), and the resulting antibody was then mixed with LysylEndopeptidase (wherein the molar ratio was 10:1). The obtained mixturewas reacted at 37° C. for 1 hour. Thereafter, TLCK (Sigma) was added tothe reaction product to a final concentration of 30 mM, so as toterminate the reaction. Subsequently, to remove Fc, the reactionsolution was added to a Protein A column (Prosep-A; Millipore), and anunadsorbed product was then recovered. The thus recovered unadsorbedfraction was concentrated, and was then purified by gel filtration(Superdex 75; GE Healthcare), so that the contained F(ab′)2 wasseparated from Fab. The obtained F(ab′)2 was concentrated and was thendialyzed against a 10 mM carbonate buffer (pH 9.5).

Subsequently, in accordance with the method of Nakane et al. (J.Histochem. Cytochem., 22, 1084, 1974), 1 mg of peroxidase (Toyobo Co.,Ltd.) was dissolved in distilled water, and 100 mM periodic aciddissolved in distilled water was then added thereto. The obtainedmixture was reacted at 25° C. for 15 minutes. After completion of thereaction, 1.5% ethylene glycol was added to the reaction solution, andthe obtained mixture was then reacted at 25° C. for 20 minutes.Thereafter, the reaction solution was dialyzed against a 1 mM acetatebuffer (pH 4.4). On the following day, a 0.2 M carbonate buffer (pH 9.5)was added with respect to 1 mg of a F1106-13-3 F(ab′)2 antibody, and 0.8mg of activated peroxidase was then mixed with the above mixture. Thethus obtained mixture was reacted at 25° C. for 2 hours. Then, 4 mg/mLsodium borohydride was added to the reaction solution, and the obtainedmixture was further reacted at 4° C. for 2 hours. The reaction solutionwas dialyzed against PBS (pH 7.4) to obtain a peroxidase-labeledantibody. The amount of the liquid was measured, and an antibodyconcentration was then calculated based on the amount of the antibodyused.

(1-2) Production of Sandwich EIA System

The S68-peptide polyclonal antibody described in InternationalPublication WO2004/044005 was diluted with D-PBS (pH 7.4), resulting ina concentration of 5 μg/mL, and 50 μL of the antibody solution was thenadded to each well of an immunoplate (Maxisorp; NUNC). The antibody wasreacted at 4° C. overnight, and it was then washed with ion exchangewater five times. Thereafter, 200 μL of D-PBS that contained 0.1%StabilGuard (SurModics, Inc) and 0.1% Tween20 was added to each well toblock it. Subsequently, D-PBS (pH 7.4) that contained 1% CD14 absorbedserum and 0.1% BSA was used as a diluent to prepare a dilution series ofsCD14-ST protein standard products each having a concentration of 0,0.015, 0.031, 0.063, 0.125, 0.25, or 0.5 ng/mL. As such a sCD14-STprotein standard product, rsCD14-ST described in InternationalPublication WO2005/108429 was used. 50 μL each of the dilution series ofthe standard products was added to each well, and the obtained mixturewas then reacted at 25° C. for 1 hour (a first reaction). Aftercompletion of the reaction, the reaction mixture was washed with anormal saline containing 0.05% Tween 20 five times. Thereafter, 50 μL ofa F1106-13-3F(ab′)2 antibody labeled with peroxidase that had beendiluted to a concentration of 0.25 μg/mL with PBS (pH 7.4) containing 2%rat serum, 1% mouse serum and 0.1% Tween 20 was added to each well. Theobtained mixture was reacted at 25° C. for 1 hour (a second reaction),and thereafter, the reaction mixture was washed five times in the samemanner as described above. Thereafter, 50 μL of a tetramethylbenzidinesolution (TMB, BioFix) was added to each well, and the obtained mixturewas then reacted at room temperature for 20 minutes. After that, 50 μLof a 0.5 M sulfuric acid solution was added to the reaction mixture toterminate the reaction. The absorbance at 450/630 nm was measured usinga plate spectrophotometer (Multiscan JX; Thermo Electron). It showed thestandard curve produced in FIG. 1.

Example 2 Measurement of sCD14-ST in Urine

By using the sandwich EIA system prepared in Example 1, concentrationsof sCD14-ST in urine samples (200-fold dilution) of 10 normal subjects(purchased from Bioreclamation, LLC) and of 6 patients with pneumoniaassociated with bacterial infection (community-acquired pneumonia)(purchased from Bioreclamation, LLC) were measured. As a result, asshown in Table 1, the average value of sCD14-ST concentration in urinesamples of normal subjects was 3338 pg/mL, and SD was 1210 pg/mL. Theaverage value of that of patients with pneumonia was 2591 to 7937 pg/mL.For reference, the concentration of sCD14-ST in a blood sample that hadbeen collected on the same date as that of a urine sample derived fromeach of the pneumonia patients was measured. As a result, a fluctuationin sCD14-ST concentrations in urine correlated to a fluctuation insCD15-ST concentrations in blood, and the concentration of sCD14-ST inurine was higher than that in blood by approximately 5 times. From theseresults, it was assumed that sCD14-ST in circulating blood would berelatively promptly concentrated and eliminated into urine. As shown inFIG. 2 in which the number of days from the day of diagnosis aspneumonia to the day of sampling was plotted on the abscissa and theconcentration of sCD14-ST on the ordinate, the smaller number of daysfrom diagnosis led to higher concentration and the larger number of daysfrom diagnosis led to smaller concentration. In general, initiation ofadministering an antibiotic within 4 hours after diagnosis of pneumoniais recommended. Thus, it was demonstrated that patients with pneumoniaassociated with bacterial infection have higher sCD14-ST concentrationin urine, and that symptomatic improvement by treatment and reduction insCD14-ST concentration in urine are correlated. That is, it wasdemonstrated that, by using the sCD14-ST concentration in urine as anindication (for example, by using an average value of normalsubjects+2SD as a cutoff value), respiratory infection associated withbacterial infection can be detected, and patients to receive anantibiotic can be selected. Also, it was shown that, when the sCD14-STconcentration in urine is lower than a reference value (for example, anaverage value of normal subjects+2SD, or for more strict conditions, anaverage value of normal subjects+SD), ending of administration of anantibiotic can be determined.

TABLE 1 Number of days sCD14-ST Sample elapsed from diagnosisconcentration No. Classification to sample collection (pg/mL) N1 Normal— 2069 N2 Normal — 2143 N3 Normal — 2550 N4 Normal — 2994 N5 Normal —5586 N6 Normal — 5252 N7 Normal — 2735 N8 Normal — 3771 N9 Normal — 2994N10 Normal — 3290 S1 Pneumonia  3 days 7937 S2 Pneumonia  4 days 7291 S3Pneumonia  7 days 5552 S4 Pneumonia 11 days 4170 S5 Pneumonia 11 days2591 S6 Pneumonia 18 days 3749

Example 3 Selection of Patients with Respiratory Infection to Receive anAntibiotic by Using the sCD14-ST Concentration as an Indication

Patients showing at least breathing difficulty or cough as a clinicalfinding and suspected to have respiratory infection are assigned to acontrol group to receive usual treatment with an antibiotic, and asCD14-ST group to receive treatment with the antibiotic by using thesCD14-ST concentration as an indication. The control group patientsreceive the antibiotic at a physician's discretion as usual. ThesCD14-ST group patients receive the antibiotic depending on a measuredvalue of sCD14-ST in a urine sample; when the measured value of sCD14-STis higher than a normal value, administration of the antibiotic isrecommended, and when the measured value of sCD14-ST is equal to thenormal value or lower than the normal value, administration of theantibiotic is not recommended.

Symptomatic improvement in both groups of patients is evaluated at 2, 4,6, or 8 weeks after initiation of the study. Administration of theantibiotic until 2 or 4 weeks after initiation of the study is alsoevaluated. As additional information, where appropriate, pneumonia,bronchitis, acute exacerbation of chronic obstructive pulmonary disease,bronchial asthma, and the like of respiratory tract infections in bothgroups of patients are checked based on X-ray shadow, blood testing,respiratory function testing, and the like.

Symptomatic improvement is evaluated as improvement of clinicalfindings. As additional end points, self-health-evaluation by patients(VAS, QOL questionnaire, and the like), and measured values of sCD14-STmay be added.

As a result, there is no difference in symptomatic improvement betweenboth groups. However, administration of the antibiotic is significantlyreduced in the sCD14-ST group. Furthermore, it is demonstrated that, inthe sCD14-ST group, the sub-group of patients with a disease oftenassociated with bacterial infection (for example, pneumonia) have ahigher percentage of receiving the antibiotic, and the other sub-groupof patients with a disease rarely associated with bacterial infection(for example, bronchial asthma) have a lower percentage of receiving theantibiotic.

Therefore, by using the sCD14-ST concentration as an indication,patients with respiratory infection to receive an antibiotic can beappropriately selected, and usage of an antibiotic (number of patientsto receive the antibiotic, amount of the antibiotic to receive, durationto receive, or number of prescriptions) can be reduced without beingdestructive to the safety and the efficacy of the antibiotic therapy.

Example 4 Optimization of Duration to Receive an Antibiotic in Patientswith Pneumonia by Using the sCD14-ST Concentration as an Indication

Patients whose condition is diagnosed as pneumonia based on clinicalfindings and to receive an antibiotic are assigned to a control group toreceive usual treatment with the antibiotic, and a sCD14-ST group toreceive treatment with the antibiotic by using the sCD14-STconcentration as an indication. The control group patients stopreceiving the antibiotic at a physician's discretion as usual. ThesCD14-ST group patients receive the antibiotic depending on a measuredvalue of sCD14-ST in a urine sample; when the measured value of sCD14-STis equal to the normal value or lower than the normal value, endingadministration of the antibiotic is recommended. The measured value ofsCD14-ST is preferably obtained over time (for example, every day afterinitiation of receiving the antibiotic).

Symptomatic improvement in both groups of patients is evaluated at 2, 4,6, or 8 weeks after initiation of administrating the antibiotic. Aperiod elapsed until administration of the antibiotic has beenterminated is also evaluated. As additional information, severity ofpneumonia in both groups of patients is determined.

Symptomatic improvement is evaluated as improvement of clinicalfindings. In particular, curing of pneumonia is preferably checked. Asadditional end points, self-health-evaluation by patients (VAS, QOLquestionnaire, and the like), and measured values of sCD14-ST may beadded.

As a result, there is no difference in symptomatic improvement betweenboth groups. However, administrating duration of the antibiotic issignificantly reduced in the sCD14-ST group.

Therefore, by using the sCD14-ST concentration as an indication, timingfor ending administration of the antibiotic can be appropriatelydetermined, and duration of administering the antibiotic can be reducedwithout being destructive to the safety and the efficacy of theantibiotic therapy.

Example 5 Measurement of sCD14-ST in Urine

Measurement conditions applied to the sandwich EIA system prepared inExample 1 were revised, and the first reaction conditions described inExample 1 were changed to 25° C. for 1 hour, and the second reactionconditions to 25° C. for 2 hours. By using this system, concentrationsof sCD14-ST in urine samples (5-fold dilution) of 9 patients withpneumonia associated with bacterial infection and of 2 patients withviral pneumonia (purchased from Bioreclamation, Inc.) were measured. Asa result, sCD14-ST concentrations in urine of patients with pneumoniaassociated with bacterial infection were 419 to 3859 pg/mL (median, 1885pg/mL), and those of patients with viral pneumonia were 115 to 517 pg/mL(median, 316 pg/mL). Accordingly, sCD14-ST concentrations in urine ofpatients with viral pneumonia were lower than the average value ofnormal subjects, and were clearly lower than those of patients withpneumonia associated with bacterial infection needing administration ofthe antibiotic (FIG. 3). Therefore, it was indicated that measuringsCD14-ST in a urine sample can distinguish respiratory infectionassociated with bacterial infection from viral respiratory infection.

Example 6 Elimination of sCD14-ST from Blood into Urine

Rate of sCD14-ST elimination from blood into urine was determined. To 3dogs (male beagle dogs, 7 or 8 months old, purchased from Kitayama LabesCo., Ltd.), recombinant sCD14-ST (rsCD14-ST described in WO 2005/108429)at a dose of 10 μg/kg was administered intravenously, and the blood andurine were collected over time until 24 hours after administration. Byusing the sandwich EIA system described in Example 1, the concentrationof sCD14-ST in blood and the amount of sCD14-ST in urine were measured.The amount of sCD14-ST in urine was calculated according to the formula:the concentration of sCD-14ST in urine (pg/mL)×the amount of urine (mL).

The blood was collected before administration, 5 minutes, 10 minutes, 30minutes, 60 minutes, 90 minutes, 120 minutes, 4 hours, and 24 hoursafter administration, and centrifuged plasma was used as the measuringsample. The urine was collected by urethral catheterization underunanesthetized conditions. As much as amount of urine remaining in thebladder was collected before administration, and 15 minutes, 30 minutes,60 minutes, 90 minutes, 120 minutes, 150 minutes, 6 hours and 24 hoursafter administration. Moreover, after completion of the urinecollection, 100 mL of a normal saline was orally administered to eachdog before administration of the sCD14-ST.

FIG. 4 illustrates the transition in sCD14-ST concentrations in bloodand the transition in sCD14-ST amounts in urine. The half-life ofsCD14-ST in blood was 25 minutes within 1 hour after administration, andthen was 58 minutes, and thus, sCD14-ST in blood showed a biphasickinetics. Concentration of sCD14-ST in blood 120 minutes afteradministration reduced to approximately 6% of the blood concentration 5minutes after administration, and sCD14-ST was completely eliminatedfrom blood 24 hours after administration. The amount of sCD14-ST inurine reached a peak 30 minutes after administration, and then, 150minutes after administration, the amount of sCD14-ST in urine reduced toapproximately 4% of that of the peak time. Twenty-four hours afteradministration, sCD14-ST completely disappeared from urine. From theseresults, it became clear that the blood sCD14-ST begins to be eliminatedinto urine within 1 hour after administration, and that most of sCD14-STis then eliminated even from urine within 3 hours after administration.The appearance and elimination of sCD14-ST in urine take place verypromptly, and are considered to sensitively reflect the movement ofsCD14-ST generated in a body by bacterial infection. That is to say, itwas demonstrated that when bacterial infection in respiratory organs isdecreased or eliminated, the sCD14-ST concentration in urine is alsoreduced rapidly, and it can be appropriately used for determination ofending administration of an antibiotic, and the like.

The invention claimed is:
 1. A method for detecting a respiratoryinfection associated with a bacterial infection in a subject in needthereof, comprising: (1) measuring soluble CD14 antigen subtype(“sCD14-ST”) in a urine sample derived from the subject; (2) comparing ameasured value of sCD14-ST with a cutoff value; (3) discriminatingbetween bacterial and viral infections based on the measured value ofsCD14-ST; wherein an increase in said measured value of sCD14-STcompared to said cutoff value is indicative of the respiratory infectionassociated with the bacterial infection and a decrease in said measuredvalue of sCD14-ST compared to said cutoff value is indicative of therespiratory infection associated with the viral infection; wherein saidcutoff value is 5,000 pg/mL; wherein the sCD14-ST is measured by asandwich immunoassay system comprising: (a) an antibody binding to apeptide comprising an amino acid sequence of SEQ ID No: 2, and (b) anantibody binding to a peptide comprising an amino acid sequence atpositions 17 to 26 of SEQ ID NO:
 3. 2. A method for detecting arespiratory infection associated with a bacterial infection in a subjectin need thereof, which comprises the following steps of: (1) measuringsCD14-ST in a urine sample derived from the subject; and (2) determiningwhether or not the subject is affected with the respiratory infectionassociated with the bacterial infection by comparing a measured value ofsCD14-ST in the sample with a cutoff value; wherein an increase in themeasured value of sCD14-ST compared to the cutoff value is indicative ofthe respiratory infection associated with the bacterial infection;wherein said cutoff value is 5,000 pg/mL; wherein the sCD14-ST ismeasured by a sandwich immunoassay system comprising: (a) an antibodybinding to a peptide comprising an amino acid sequence of SEQ ID No: 2,and (b) an antibody binding to a peptide comprising an amino acidsequence at positions 17 to 26 of SEQ ID NO:
 3. 3. The method accordingto claim 1 or 2, wherein the respiratory infection associated with thebacterial infection is a lower respiratory tract infection or pneumonia.4. A method for selecting a patient with a respiratory infection toreceive an antibiotic, comprising: (1) measuring sCD14-ST in a urinesample derived from the patient; and (2) determining whether or not thepatient is affected with the respiratory infection associated with abacterial infection by using a measured value of sCD14-ST in the samplesas an indication, wherein an increased measured value of sCD14-STcompared to a cutoff value is indicative of the respiratory infectionassociated with the bacterial infection; (3) selecting said patient withsaid increased measured value of sCD14-ST to receive an antibiotic;wherein said cutoff value is 5,000 pg/mL; wherein the sCD14-ST ismeasured by a sandwich immunoassay system comprising: (a) an antibodybinding to a peptide comprising an amino acid sequence of SEQ ID No: 2,and (b) an antibody binding to a peptide comprising an amino acidsequence at positions 17 to 26 of SEQ ID NO:
 3. 5. The method accordingto claim 4, wherein the respiratory infection is a lower respiratorytract infection or pneumonia.
 6. A method for determining the timing forending administration of an antibiotic to a patient with a respiratoryinfection receiving the antibiotic, wherein a measured value of sCD14-STin a urine sample derived from the patient is used as an indication,wherein a decrease in the measured value of sCD14-ST compared to acutoff value is indicative of the timing for ending administration ofthe antibiotic to the patient; wherein said cutoff value is 5000 pg/mL;wherein the sCD14-ST is measured by a sandwich immunoassay systemcomprising: (a) an antibody binding to a peptide comprising an aminoacid sequence of SEQ ID No: 2, and (b) an antibody binding to a peptidecomprising an amino acid sequence at positions 17 to 26 of SEQ ID NO: 3.7. A method for determining the timing for ending administration of anantibiotic to a patient with a respiratory infection receiving theantibiotic, which comprises the following steps of: (1) measuringsCD14-ST in a urine sample derived from the patient; (2) comparing ameasured value of sCD14-ST in the sample with a cutoff value; and (3)when the measured value of the sample is lower than the cutoff value,determining to end administration of the antibiotic; wherein said cutoffvalue is 5000 pg/mL; wherein the sCD14-ST is measured by a sandwichimmunoassay system comprising: (a) an antibody binding to a peptidecomprising an amino acid sequence of SEQ ID No: 2, and (b) an antibodybinding to a peptide comprising an amino acid sequence at positions 17to 26 of SEQ ID NO:
 3. 8. A method for selecting a patient to endadministration of an antibiotic from the patient with a respiratoryinfection receiving the antibiotic comprising using a measured value ofsCD14-ST in a urine sample derived from the patient as an indication;wherein a decrease in the measured value of sCD14-ST compared to acutoff value is indicative of the patient to end administration of theantibiotic; wherein said cutoff value is 5000 pg/mL; wherein thesCD14-ST is measured by a sandwich immunoassay system comprising: (a) anantibody binding to a peptide comprising an amino acid sequence of SEQID No: 2, and (b) an antibody binding to a peptide comprising an aminoacid sequence at positions 17 to 26 of SEQ ID NO:
 3. 9. A method forselecting a patient for whom to end administration of an antibiotic,wherein the patient has a respiratory infection and is receiving theantibiotic, which comprises the following steps of: (1) measuringsCD14-ST in a urine sample derived from a patient; (2) comparing ameasured value of sCD14-ST in the sample with a cutoff value; and (3)when the measured value of the sample is lower than the cutoff value,determining to end administration of the antibiotic; wherein said cutoffvalue is 5000 pg/mL; wherein the sCD14-ST is measured by a sandwichimmunoassay system comprising: (a) an antibody binding to a peptidecomprising an amino acid sequence of SEQ ID No: 2, and (b) an antibodybinding to a peptide comprising an amino acid sequence at positions 17to 26 of SEQ ID NO:
 3. 10. The method according to any one of claims6-9, wherein the respiratory infection is a lower respiratory tractinfection or pneumonia.
 11. A method for treating a respiratoryinfection associated with a bacterial infection, which comprises thefollowing steps of: (1) measuring sCD14-ST in a urine sample derivedfrom a patient; (2) selecting the patient to receive an antibiotic byusing a measured value of sCD14-ST in the sample as an indication; and(3) administering the antibiotic to the selected patient; wherein anincrease in the measured value of sCD14-ST compared to a cutoff value isindicative of the patient to receive the antibiotic; wherein said cutoffvalue is 5000 pg/mL; wherein the sCD14-ST is measured by a sandwichimmunoassay system comprising: (a) an antibody binding to a peptidecomprising an amino acid sequence of SEQ ID No: 2, and (b) an antibodybinding to a peptide comprising an amino acid sequence at positions 17to 26 of SEQ ID NO:
 3. 12. The method according to claim 11, wherein thestep of selecting the patient to receive the antibiotic by using themeasured value of sCD14-ST in the sample as the indication comprises thefollowing steps of: (1) comparing the measured value of sCD14-ST in thesample with a cutoff value; and (2) selecting the patient to receive theantibiotic whose measured value in the sample is higher than the cutoffvalue; wherein said cutoff value is 5000 pg/mL; wherein the sCD14-ST ismeasured by a sandwich immunoassay system comprising: (a) an antibodybinding to a peptide comprising an amino acid sequence of SEQ ID No: 2,and (b) an antibody binding to a peptide comprising an amino acidsequence at positions 17 to 26 of SEQ ID NO:
 3. 13. The method accordingto claim 11, which further comprises the following steps of: (1)measuring sCD14-ST in the urine sample derived from the patientreceiving the antibiotic until determining to end administration of theantibiotic; (2) comparing the measured value of sCD14-ST in the samplewith a cutoff value; and (3) when the measured value of the sample islower than the cutoff value, determining to end administration of theantibiotic; wherein said cutoff value is 5000 pg/mL; wherein thesCD14-ST is measured by a sandwich immunoassay system comprising: (a) anantibody binding to a peptide comprising an amino acid sequence of SEQID No: 2, and (b) an antibody binding to a peptide comprising an aminoacid sequence at positions 17 to 26 of SEQ ID NO:
 3. 14. The methodaccording to claim 11, wherein the respiratory infection associated withthe bacterial infection is a lower respiratory tract infection orpneumonia.
 15. A method for detecting a respiratory infection associatedwith a bacterial infection in a subject in need thereof, comprisingmeasuring soluble CD14 antigen subtype (“sCD14-ST”) in a urine samplederived from the subject; wherein an increase in a measured value ofsCD14-ST is indicative of the respiratory infection associated with thebacterial infection; wherein the sCD14-ST level above a cutoff valueindicates a need for the subject to receive an antibiotic, wherein thecutoff value is 5,000 pg/ml; wherein the sCD14-ST is measured by asandwich immunoassay system comprising: (a) an antibody binding to apeptide comprising an amino acid sequence of SEQ ID No: 2, and (b) anantibody binding to a peptide comprising an amino acid sequence atpositions 17 to 26 of SEQ ID NO:
 3. 16. A method of treating arespiratory infection associated with a bacterial infection comprisingadministering an antibiotic to a patient having an sCD14-ST level inurine above a cutoff value; wherein the cutoff value is 5,000 pg/ml;wherein the sCD14-ST is measured by a sandwich immunoassay systemcomprising: (a) an antibody binding to a peptide comprising an aminoacid sequence of SEQ ID No: 2, and (b) an antibody binding to a peptidecomprising an amino acid sequence at positions 17 to 26 of SEQ ID NO: 3.